The control of both hepatic gluconeogenesis and hepatic mixed function oxidation (drug metabolism) are interrelated and under hormonal control. This interrelationship and its control are greatly affected by diabetes. The overall objective of the proposed research is to determine the nature of these integrated control mechanisms and changes in the composition of the drug metabolism system that occur during diabetes. The specific objectives include the identification of the diabetes-induced cytochrome P450 microsomal composition, determination of the mechanism of influence of the gluconeogenic process on hepatic mixed function oxidation, and the reciprocal influence. Isolated perfused normal and diabetic rat and guinea pig livers and hepatic microsomes will be the focus of the integrated research procedures used to study these control phenomena. Other procedures to be used include various chromatographic techniques.